The studies proposed herein are a continuation of our work over the past eight years; 1) to characterize the cause(s) of the abnormal insulin and glucagon secretion in human diabetes. 2) to quantitate the relative consequences of insulin deficiency and glucagon excess on glucose and ketone body metabolism in human diabetes. 3) to determine the interaction of other hormones on insulin and glucagon action in man. Specifically, we plan to study: 1) anomeric specificity of A and B cell sensitivity to glucose, 2) effect of hypoglycemia on A and B cell function, 3) effect of nonglucose secretagogues on insulin secretion, 4) effects of prolonged hyperglycemia on A and B cell function, 5) effects of hyperglucagonemia and changes in plasma glucose concentration on glucose clearance, 6) effect of insulin and glucagon on ketone body metabolism, 7) glucose and ketone body turnovers in the diabetes of pancreatectomized man, 8) effects of epinephrine on glucose and ketone body metabolism, 9) growth hormone and cortisol effect on insulin receptors and insulin sensitivity in vivo, 10) studies on the mechanisms of changes in insulin receptor function due to growth hormone and cortisol, 11) interaction of insulin, glucagon, and epinephrine on glucose and ketone body metabolism, 12) influence of cortisol and growth hormone on metabolism responses to glucagon. These studies will utilize newly set up techniques for the determination of insulin receptor function, in vivo insulin sensitivity (insulin dose response curves) and isotopic estimation of ketone body turnover as well as previously established methods (e.g., isotopic glucose turnovers and various radioimmunoassays, bioassays, and chromatography).